MicroRNAs (miRNAs) comprise a large family of small (22 nt) noncoding RNAs that have been implicated in translational repression of target mRNAs bearing imperfectly complementary sequences in their 3'untranslated regions. Disturbances in miRNA-dependent processes have been proposed to contribute to the etiology of mental disorders, but the role of miRNAs in synaptic and cognitive function in the mammalian brain is entirely unknown. The broad, long-term objective of this application is to understand the role of miRNAs in neural processes underlying cognition and behavior, particularly regulation of neuronal gene expression and synaptic plasticity in the postnatal brain. We recently employed a multidisciplinary approach to demonstrate a crucial role for translational control in long-lasting synaptic plasticity and memory. Our findings suggested that general upregulation of local protein synthesis through the MARK and mTOR pathways is necessary for persistent modifications of synaptic connectivity and associated cognitive processes. While these results point to the importance of general translational mechanisms, the translational response to synaptic activation is likely to be modulated by mRNA-specific mechanisms mediated by cis-acting elements, such as miRNA target sequences. Therefore, we propose to test the hypothesis that miRNAs play essential roles in the regulation of neuronal gene expression, synaptic plasticity and cognition in the postnatal brain. More specifically, we postulate that miRNA-dependent translational control selectively regulates the protein synthesis-dependent consolidation of synaptic plasticity and memory. To address these questions, we are employing a conditional genetic approach to inactivate Dicer and abolish miRNA expression in neurons of the postnatal forebrain. Multidisciplinary analysis of the phenotypes caused by conditional ablation of miRNA expression will allow us to evaluate the global contribution of miRNAs to neural processes in the postnatal brain. Our Specific Aims focus on the role of miRNAs in (1) neuronal activity-dependent translational control in primary hippocampal neurons, (2) spatiotemporal patterns of expression of specific proteins implicated in synaptic modifications in the postnatal brain, (3) protein synthesis-dependent and -independent phases of hippocampal synaptic plasticity, and (4) behaviors relevant to mental disorders, particularly protein synthesis-dependent and -independent phases of hippocampus- and amygdala-dependent memory. Accomplishment of the proposed studies should yield important insights into the role of miRNAs in brain function, and the possible involvement of altered miRNA-dependent processes in the pathogenesis of mental disorders.